Journal
MOLECULAR PSYCHIATRY
Volume 23, Issue 11, Pages 2192-2208Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41380-017-0002-4
Keywords
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Funding
- Medical Research Council (UK) [MR/L014815/1, MR/J002739/1]
- National Institute for Health Research Mental Health Biomedical Research Centre in Mental Health at South London and Maudsley NHS Foundation Trust
- King's College London
- Eranet Neuron 'Inflame-D'
- Ministry of Health (MoH)
- Italian Ministry of University and Research (PRIN)
- Fondazione CARIPLO [2012-0503]
- National Institute of Mental Health [MH071538]
- Finish Academy to Professor [7631758, 284859, 2848591, 312670, 269925, 311617]
- [2015SKN9YT]
- Academy of Medical Sciences (AMS) [AMS-SGCL5-Mondelli] Funding Source: researchfish
- Medical Research Council [MR/J002739/1, MR/N029488/1, G108/603] Funding Source: researchfish
- National Institute for Health Research [CL-2008-17-005, NF-SI-0616-10074] Funding Source: researchfish
- Novo Nordisk Fonden [NNF15OC0016362] Funding Source: researchfish
- MRC [MR/L014815/1, MR/J002739/1, G108/603, MR/N029488/1] Funding Source: UKRI
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To date, gene-environment (GxE) interaction studies in depression have been limited to hypothesis-based candidate genes, since genome-wide (GWAS)-based GxE interaction studies would require enormous datasets with genetics, environmental, and clinical variables. We used a novel, cross-species and cross-tissues omics approach to identify genes predicting depression in response to stress in GxE interactions. We integrated the transcriptome and miRNome profiles from the hippocampus of adult rats exposed to prenatal stress (PNS) with transcriptome data obtained from blood mRNA of adult humans exposed to early life trauma, using a stringent statistical analyses pathway. Network analysis of the integrated gene lists identified the Forkhead box protein O1 (FoxO1), Alpha-2-Macroglobulin (A2M), and Transforming Growth Factor Beta 1 (TGF-beta 1) as candidates to be tested for GxE interactions, in two GWAS samples of adults either with a range of childhood traumatic experiences (Grady Study Project, Atlanta, USA) or with separation from parents in childhood only (Helsinki Birth Cohort Study, Finland). After correction for multiple testing, a meta-analysis across both samples confirmed six FoxO1 SNPs showing significant GxE interactions with early life emotional stress in predicting depressive symptoms. Moreover, in vitro experiments in a human hippocampal progenitor cell line confirmed a functional role of FoxO1 in stress responsivity. In secondary analyses, A2M and TGF-beta 1 showed significant GxE interactions with emotional, physical, and sexual abuse in the Grady Study. We therefore provide a successful 'hypothesis-free' approach for the identification and prioritization of candidate genes for GxE interaction studies that can be investigated in GWAS datasets.
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